Cell cycle progression requires the E3 ubiquitin ligase anaphase-promoting complex (APC/C), which uses the substrate adaptors CDC20 and CDH1 to target proteins for proteasomal degradation. The APCCDH1 substrate cyclin A is critical for the G1/S transition and, paradoxically, accumulates even when APCCDH1 is active. We show that the deubiquitinase USP37 binds CDH1 and removes degradative polyubiquitin from cyclin A. USP37 was induced by E2F transcription factors in G1, peaked at G1/S, and was degraded in late mitosis. Phosphorylation of USP37 by CDK2 stimulated its full activity. USP37 overexpression caused premature cyclin A accumulation in G1 and accelerated S phase entry, whereas USP37 knockdown delayed these events. USP37 was inactive in mitosis because it was no longer phosphorylated by CDK2. Indeed, it switched from an antagonist to a substrate of APCCDH1 and was modified with degradative K11-linked polyubiquitin.
Graphical Abstract
Highlights
► USP37 binds CDH1, but not CDC20 ► USP37 regulates cell cycle by deubiquitinating cyclin A ► CDK2/cyclin A phosphorylates USP37 and maximizes its DUB activity ► USP37 is ubiquitinated by APCCDH1 in late mitosis and early G1 phase